Abstract

Although primary dystonia is defined by its characteristic motor manifestations, non-motor signs and symptoms have increasingly been recognized in this disorder. Recent neuroimaging studies have related the motor features of primary dystonia to connectivity changes in cerebello-thalamo-cortical pathways. It is not known, however, whether the non-motor manifestations of the disorder are associated with similar circuit abnormalities. To explore this possibility, we used functional magnetic resonance imaging to study primary dystonia and healthy volunteer subjects while they performed a motion perception task in which elliptical target trajectories were visually tracked on a computer screen. Prior functional magnetic resonance imaging studies of healthy subjects performing this task have revealed selective activation of motor regions during the perception of 'natural' versus 'unnatural' motion (defined respectively as trajectories with kinematic properties that either comply with or violate the two-thirds power law of motion). Several regions with significant connectivity changes in primary dystonia were situated in proximity to normal motion perception pathways, suggesting that abnormalities of these circuits may also be present in this disorder. To determine whether activation responses to natural versus unnatural motion in primary dystonia differ from normal, we used functional magnetic resonance imaging to study 10 DYT1 dystonia and 10 healthy control subjects at rest and during the perception of 'natural' and 'unnatural' motion. Both groups exhibited significant activation changes across perceptual conditions in the cerebellum, pons, and subthalamic nucleus. The two groups differed, however, in their responses to 'natural' versus 'unnatural' motion in these regions. In healthy subjects, regional activation was greater during the perception of natural (versus unnatural) motion (P < 0.05). By contrast, in DYT1 dystonia subjects, activation was relatively greater during the perception of unnatural (versus natural) motion (P < 0.01). To explore the microstructural basis for these functional changes, the regions with significant interaction effects (i.e. those with group differences in activation across perceptual conditions) were used as seeds for tractographic analysis of diffusion tensor imaging scans acquired in the same subjects. Fibre pathways specifically connecting each of the significant functional magnetic resonance imaging clusters to the cerebellum were reconstructed. Of the various reconstructed pathways that were analysed, the ponto-cerebellar projection alone differed between groups, with reduced fibre integrity in dystonia (P < 0.001). In aggregate, the findings suggest that the normal pattern of brain activation in response to motion perception is disrupted in DYT1 dystonia. Thus, it is unlikely that the circuit changes that underlie this disorder are limited to primary sensorimotor pathways.

The visual motion perception task. Target motion (dots) based on the relationship between instantaneous velocity and the radius of curvature of the elliptical trajectory (see text). In this display, R and r represent the radii of minimum (red) and maximum (blue) curvature for the trajectory, and V1 and V2 represent target velocity at the two points, where V1 = KRβ and V2 = Krβ. The ‘natural’ movement profile (β = 1/3, for which V1 > V2) defined by increasing target velocity as the path straightens and slowing of velocity as the path becomes more curved. The ‘unnatural’ profiles are defined by either fixed target velocity (β = 0, for which V1 = V2) or by a reversal (β = −1/3, for which V1 < V2) of the ‘natural’ profile, such that target velocity increases rather than declines as the point of maximal curvature is reached.

Regions with abnormally elevated perception-related activation responses in DYT1 dystonia. Left: Regions with significant main effect of group (dystonia > healthy subjects) were identified by voxel-wise searches of scans acquired during the perception of natural and unnatural target motion (arrows). Right: Group differences were also sought by comparing scans acquired separately in each of the perceptual conditions. In both sets of contrasts (), activation responses in parietal and visual association regions were greater in DYT1 dystonia relative to healthy subjects. Increased perception-related activation in DYT1 dystonia was most pronounced in the β = −1/3 condition (arrows), suggesting dominance of neural responses to unnatural motion in the disease group. The colour bar represents voxels thresholded at T = 2.9 (P < 0.005, uncorrected).

Group differences in activation profiles across task conditions. (A) Group differences in activation responses across perceptual conditions were assessed on a voxel by voxel basis. Significant group × condition interaction effects () were found in the cerebellum, and in the ponto-mesencephalic region extending into the region of the thalamus, subthalamic nucleus (STN), and globus pallidus (GP). The colour bar represents voxels thresholded at T = 3.2 (P < 0.001, uncorrected). (B) Analysis of the data from each of the significant clusters revealed consistent within-subject activation increases during the perception of natural versus unnatural motion in normal individuals (blue lines) and concomitant reductions in DYT1 dystonia subjects (red lines). Brackets on the left side of each graph indicate group differences between DYT1 and normal for the unnatural [β = (0) + (−1/3)] condition. Brackets above each graph indicate the difference between natural and unnatural conditions in the DYT1 dystonia group; those below each graph represent the corresponding difference in healthy subjects (*P < 0.05; **P < 0.01; ***P < 0.001; post hoc Bonferroni tests).

Reductions in ponto-cerebellar fibre tracts in DYT1 dystonia subjects. Reconstruction of ponto-cerebellar projection pathways in (A) healthy subjects and (B) DYT1 dystonia patients; fewer visualized fibre tracts were evident in the disease group (see text). For each group, a spherical volume of interest of radius 5 mm was centred in the right pons (red) at the coordinates of the maximal group × condition functional MRI interaction effect in that region ([12, −28, −30]; A, right). This volume of interest was used as a seed region in magnetic resonance DTI scans from the same subjects to reconstruct pontine projections to the cerebellar cortex on a group-wise basis. Reconstructed fibre tracts linking the right pontine volume of interest (red), and its left pontine mirror-image volume of interest (orange), to the corresponding cerebellar hemispheres were seen to pass through the middle cerebellar peduncle (MCP). The estimated number of visualized fibre tracts for each bundle is provided on each panel. A mean reduction in fibre tracts of 19.9% was observed for DYT1 dystonia relative to healthy control subjects. (C) Area of significantly reduced fractional anisotropy (FA) observed in right deep cerebellar white matter (red) and in the contralateral left mirror region (orange). This abnormality was previously identified in a voxel-wise contrast of fractional anisotropy maps from DYT1 mutation carriers and gene negative control subjects (). (D) Individual fractional anisotropy values from the genotypic cerebellar white matter region (C) were correlated with corresponding pontine measures from the same individuals. A significant correlation (r = 0.72, P = 0.02; Pearson’s product-moment correlation coefficient) was observed between the pontine and cerebellar fractional anisotropy values in the DYT1 dystonia patients but not in the healthy volunteer subjects (see text). The individual fractional anisotropy values computed for each region were right/left averaged. The resulting measures were standardized (z-scored) with respect to the control values such that the distribution in the healthy subjects had a mean equal to 0 with a standard deviation of 1. VOI = volume of interest.